title: Effect of metformin on residual cells after chemotherapy in a human lung adenocarcinoma cell line.
abstract: Cancer chemotherapy, including molecular targeted therapy, has major limitations because it does not kill all the cancer cells; the residual cells survive until they acquire chemoresistance. In the present study, the combined effects of metformin and gefitinib were examined in vivo in a mouse xenograft model, inoculated with a human lung adenocarcinoma cell line that possesses an activating epidermal growth factor receptor mutation. The mechanism of the interaction was further elucidated in vitro. Metformin did not suppress the growth of already established tumors, nor did metformin augment tumor shrinkage by gefitinib. However, metformin significantly suppressed the regrowth of the tumor after effective treatment with gefitinib, suggesting the specific effect of metformin on the residual cells. Cytotoxicity of metformin was characterized by the absence of apoptosis induction and unremarkable cell cycle shift in vitro. The residual cell population after treatment with gefitinib was characterized by enriched cells with high expression of CD133 and CD24. Metformin was still effective on this specific cell population. Targeting residual cells after chemotherapy may represent an effective novel strategy for the treatment of cancer. Elucidating the mechanism of metformin cytotoxicity provides insights into future development of anticancer therapeutics.
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kitazono
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takiguchi
authors.forename: Hironori
authors.initials: H
authors.lastname: Ashinuma
authors.forename: Miyako
authors.initials: M
authors.lastname: Saito-Kitazono
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitamura
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Chiba
authors.forename: Emiko
authors.initials: E
authors.lastname: Sakaida
authors.forename: Ikuo
authors.initials: I
authors.lastname: Sekine
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kurosu
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Sakao
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanabe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
mesh_terms: D000071916:AC133 Antigen; D000230:Adenocarcinoma / Q000188:drug therapy*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051927:CD24 Antigen / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D000077156:Gefitinib; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy*; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010455:Peptides; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D051927:CD24 Antigen; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D007004:Hypoglycemic Agents; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D008687:Metformin; D066246:ErbB Receptors; D000077156:Gefitinib